WO2018022664A1 - Compositions de neuromodulation et méthodes thérapeutiques associées pour le traitement de maladies inflammatoires et auto-immunes - Google Patents

Compositions de neuromodulation et méthodes thérapeutiques associées pour le traitement de maladies inflammatoires et auto-immunes Download PDF

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WO2018022664A1
WO2018022664A1 PCT/US2017/043802 US2017043802W WO2018022664A1 WO 2018022664 A1 WO2018022664 A1 WO 2018022664A1 US 2017043802 W US2017043802 W US 2017043802W WO 2018022664 A1 WO2018022664 A1 WO 2018022664A1
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modulator
receptor
neuropeptide
cell
neurome
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PCT/US2017/043802
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WO2018022664A8 (fr
Inventor
Erica WEINSTEIN
Jordi MATA-FINK
Avak Kahvejian
Noubar B. Afeyan
Laura Kristina JEANBART
Alexandra LANTERMANN
Jonathan Barry HUROV
Manuel Andreas FANKHAUSER
Chengyi J. SHU
Eric Franklin ZHU
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Flagship Pioneering, Inc.
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Priority to EP17835144.1A priority Critical patent/EP3506926A4/fr
Priority to US16/320,321 priority patent/US20210283217A1/en
Publication of WO2018022664A1 publication Critical patent/WO2018022664A1/fr
Publication of WO2018022664A8 publication Critical patent/WO2018022664A8/fr

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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Definitions

  • the invention relates to the discovery that modulation of neurological signaling pathways can modulate an immune response and, e.g., can be used to treat immunological disorders, inflammatory diseases, and infections. Accordingly, the present invention provides methods for treating inflammatory or autoimmune diseases or conditions or infections using neuromodulating agents. The invention also features methods of modulating an immune response or immune cell activities in a subject or in isolated immune cells.
  • the invention provides a method of treating a subject with a disease
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having a disease characterized by immune dysregulation by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject with a disease characterized by immune dysregulation by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having a disease characterized by immune dysregulation by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a
  • neuropeptide signaling modulator a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating an immune response in a subject by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating an immune response in a subject by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject with an autoimmune disease by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an autoimmune disease by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject with an autoimmune disease by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an autoimmune disease by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the autoimmune disease is Type 1 diabetes, and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the autoimmune disease is multiple sclerosis (MS)
  • the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the autoimmune disease is systemic lupus erythematosus (SLE), and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the autoimmune disease is Celiac disease, and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a
  • the autoimmune disease is inflammatory bowel disease (IBD)
  • the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the autoimmune disease is ulcerative colitis
  • the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating inflammation in a subject by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an inflammatory condition by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating inflammation in a subject by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an inflammatory condition by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the inflammation or inflammatory condition is glomerulonephritis and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the inflammation or inflammatory condition is Hirschsprung's Disease and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject with an infection by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an infection by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject with an infection by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of treating a subject identified as having an infection by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is a methicillin resistant Staphylococcus aureus infection and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is a neuromodulating agent selected from the
  • Neisseria gonorrhoeae infection and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is an aspergillus infection and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the infection is a human immunodeficiency virus (HIV) infection and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the method includes contacting an immune cell from column 2 of Table 12 with an effective amount of a neuromodulating agent that modulates a corresponding gene in column 1 of Table 12.
  • the method includes modulating an immune cell activity.
  • the method includes modulating lymph node innervation, modulating development of high endothelial venules (HEVs), or modulating the development of ectopic or tertiary lymphoid organs (TLOs)
  • HEVs high endothelial venules
  • TLOs tertiary lymphoid organs
  • the immune cell activity is activation, proliferation, phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), antigen presentation, lymph node homing, lymph node egress, differentiation, degranulation, polarization, cytokine production, recruitment, or migration.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cell-mediated phagocytosis
  • the activation, proliferation, phagocytosis, ADCC, ADCP, antigen presentation, lymph node homing, lymph node egress, differentiation, degranulation, polarization, cytokine production, recruitment, migration, lymph node innervation, development of HEVs, or development of TLOs is increased.
  • polarization toward an M1 phenotype is increased. In some embodiments, polarization toward an M2 phenotype is increased. In some embodiments, the activation, proliferation, phagocytosis, ADCC, ACCP, antigen presentation, lymph node homing, lymph node egress, differentiation,
  • cytokines are pro-inflammatory cytokines, anti-inflammatory cytokines, or proliferative cytokines.
  • recruitment or migration is directed toward a site of inflammation or infection.
  • migration is directed away from a site of inflammation or infection.
  • recruitment or migration is directed toward a lymph node or secondary lymphoid organ.
  • migration is directed away from a lymph node or secondary lymphoid organ.
  • the immune cell is selected from the group including a T cell, a cytotoxic T cell, a monocyte, a peripheral blood hematopoietic stem cell, a macrophage, an antigen presenting cell, a Natural Killer cell, a mast cell, a neutrophil, an eosinophil, a basophil, a Natural Killer T cell, a B cell, a dendritic cell, and a regulatory T cell.
  • the immune cell is a T cell.
  • the immune cell is a macrophage.
  • the immune cell is a Natural Killer (NK) cell.
  • the immune cell is a dendritic cell.
  • the immune cell is a regulatory T cell (Treg).
  • the invention provides a method of modulating innervation of a lymph node or lymphoid organ by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating innervation of a lymph node or lymphoid organ, the method comprising administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating development of high endothelial venules (HEVs) or ectopic or tertiary lymphoid organs by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • HEVs high endothelial venules
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating development of HEVs or ectopic or tertiary lymphoid organs by administering with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • development of HEVs or ectopic or tertiary lymphoid organs is increased. In some embodiments, development of HEVs or ectopic or tertiary lymphoid organs is decreased.
  • the invention provides a method of modulating T cell cytokine production by contacting a T cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating T cell cytokine production by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • T cell cytokine production of pro-inflammatory or pro-survival cytokines is increased. In some embodiments, T cell cytokine production of pro-inflammatory cytokines is decreased. In some embodiments, T cell cytokine production of anti-inflammatory cytokines is increased.
  • the invention provides a method of modulating macrophage polarization by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of modulating macrophage polarization by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • macrophages are polarized toward an M2 phenotype. In some embodiments, macrophages are polarized toward an M1 phenotype.
  • the invention provides a method of decreasing T cell pro-inflammatory cytokine production by contacting a T cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing T cell pro-inflammatory cytokine production by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing pro-inflammatory cytokine levels by contacting a T cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing pro-inflammatory cytokine levels by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the pro-inflammatory cytokine is interferon gamma (IFNy), interleukin-5 (IL-5), IL-6, IL-4, IL-1 ⁇ , IL-13, or tumor necrosis factor alpha (TNFa).
  • IFNy interferon gamma
  • IL-5 interleukin-5
  • IL-6 interleukin-6
  • IL-4 interleukin-4
  • IL-1 ⁇ tumor necrosis factor alpha
  • TNFa tumor necrosis factor alpha
  • the pro-inflammatory cytokine is IFNy. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is TNFa. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL-13. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL-4. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL-1 ⁇ .
  • the pro-inflammatory cytokine is an activator of allergic response selected from the group including IL-4 and IL-13. In some embodiments, the proinflammatory cytokine is IL-4.
  • the invention provides a method of increasing T cell pro-inflammatory cytokine production by contacting a T cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of increasing T cell pro-inflammatory cytokine production by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of increasing pro-inflammatory cytokine levels by contacting a T cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of increasing pro-inflammatory cytokine levels by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the pro-inflammatory cytokine is IFNy, IL-5, IL-6, IL-4, IL-1 ⁇ , IL-13, or TNFa. In some embodiments of any of the above aspects, the proinflammatory cytokine is IFNy. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is TNFa. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL- 13. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL-4. In some embodiments of any of the above aspects, the pro-inflammatory cytokine is IL-1 ⁇ .
  • the pro-inflammatory is a cytokine that activates the anti-parasitic immune response selected from the group including IL-4 and IL-13. In some embodiments, the pro-inflammatory cytokine is IL-4.
  • the invention provides a method of decreasing macrophage polarization toward an M1 phenotype by contacting a macrophage with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing macrophage polarization toward an M1 phenotype by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of increasing macrophage polarization toward an M1 phenotype by contacting a macrophage with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of increasing macrophage polarization toward an M1 phenotype by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing CCR7+ T cell numbers in secondary lymphoid organs by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing CCR7+ T cell numbers in sites of inflammation by contacting CCR7+ T cells with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing CCR7+ T cell numbers in sites of inflammation by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the method includes decreasing CCR7+ T cell proliferation. In some embodiments of any of the above aspects, the method includes decreasing CCR7+ T cell migration to secondary lymphoid organs. In some embodiments of any of the above aspects, the method includes decreasing CCR7+ T cell migration to sites of inflammation.
  • the invention provides a method of increasing the number of CCR7+ T cells in a lymph node by contacting a CCR7+ T cell with an effective amount of a dopamine agonist.
  • the invention provides a method of increasing the number of CCR7+ T cells in a lymph node by administering an effective amount of a dopamine agonist.
  • the method includes increasing CCR7+ T cell proliferation. In some embodiments of any of the above aspects, the method includes increasing CCR7+ T cell lymph node homing.
  • the invention provides a method of decreasing immune cell cytotoxicity by contacting an immune cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the invention provides a method of decreasing immune cell cytotoxicity by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the cytotoxicity is antibody-dependent cell- mediated cytotoxicity.
  • the immune cell is an NK cell.
  • the invention provides a method of decreasing NK cell activity or NK cell lytic function by contacting an NK cell with an effective amount a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.
  • the pro-inflammatory cytokine is IL-1 ⁇ , IL-5,
  • the pro-survival cytokine is IL-2, IL-4, IL-6, IL-7, or IL-1 5. In some embodiments of any of the above aspects, the pro-survival cytokine is IL-2, IL-4, IL-6, IL-7, or IL-1 5. In some
  • the anti-inflammatory cytokine is IL-4, IL-10, IL-1 1 , IL-13, IFNa, or TGFp.
  • the inflammatory or autoimmune disease or condition is Graves' disease, SLE, type 1 diabetes, MS, plaque psoriasis, rheumatoid arthritis (RA), asthma, myasthenia gravis, IBD, ulcerative colitis (UC), Hirschsprung's disease-associated enterocolitis (HAEC), burn, fibrosis, allergy, allergic dermatitis, pancreatitis, NASH, fatty liver disease, atherosclerosis, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, glomerulonephritis, ischemia- reperfusion injury, allograft rejection, Crohn's disease, Celiac disease, food allergy, or atopic dermatitis.
  • Graves' disease SLE, type 1 diabetes, MS, plaque psoriasis, rheumatoid arthritis (RA), asthma, myasthenia gravis, IBD, ulcerative colitis (UC), Hirschsprung's disease-associated enterocolitis
  • the infection is a persistent viral infection, bacterial infection, fungal infection, mycoplasma infection or parasitic infection.
  • the neuromodulating agent is a dopamine agonist, adrenergic agonist, nicotinic agonist, muscarinic agonist, serotonin agonist, glutamate receptor agonist, histamine agonist, cannabinoid receptor agonist, purinergic receptor agonist, GABA agonist, neuropeptide Y receptor agonist, somatostatin receptor agonist, CGRP receptor agonist, tachykinin receptor agonist, VIP receptor agonist, opioid agonist, oxytocin receptor agonist, or vasopressin receptor agonist.
  • the agonist is selected from an agonist listed in Tables 2A-2L.
  • the agonist is a dopamine agonist listed in Table 2A or 2C.
  • the dopamine agonist is dopamine, quinpirole dopexamine, bromocriptine, lisuride, pergolide, cabergoline, quinagolide, apomorphine, ropinirole, pramipexole, or piribedil.
  • the agonist is an adrenergic agonist listed in Table 2A or 2B. In some embodiments, the adrenergic agonist is
  • the neuromodulating agent is a dopamine antagonist, adrenergic antagonist, nicotinic antagonist, muscarinic antagonist, serotonin antagonist, glutamate receptor antagonist, histamine antagonist, cannabinoid receptor antagonist, purinergic receptor antagonist, GABA antagonist, neuropeptide Y receptor antagonist, somatostatin receptor antagonist, CGRP receptor antagonist, tachykinin receptor antagonist, VIP receptor antagonist, opioid antagonist, oxytocin receptor antagonist, or vasopressin receptor antagonist.
  • the antagonist is selected from an antagonist listed in Tables 2A-2L.
  • the antagonist is a dopamine antagonist listed in Table 2A or 2C.
  • the dopamine antagonist is haloperidol or L-741 ,626.
  • the antagonist is a beta adrenergic antagonist listed in Table 2A or 2B.
  • the beta adrenergic antagonist is propranolol or nadolol.
  • the neuromodulating agent is neuropeptide Y, CGRP, somatostatin, bombesin, cholecystokinin, dynorphin, enkephalin, endorphin, gastrin glucagon, melatonin, motilin, neurokinin A, neurokinin B, orexin, oxytocin, pancreatic peptide, peptide YY, substance P, or vasoactive intestinal peptide.
  • the neuromodulating agent is neuropeptide Y.
  • the neuromodulating agent is CGRP.
  • the neuromodulating agent is a neuropeptide Y, CGRP, somatostatin, bombesin, cholecystokinin, dynorphin, enkephalin, endorphin, gastrin glucagon, melatonin, motilin, neurokinin A, neurokinin B, orexin, oxytocin, pancreatic peptide, peptide YY, substance P, or vasoactive intestinal peptide blocking antibody.
  • the neuropeptide Y CGRP, somatostatin, bombesin, cholecystokinin, dynorphin, enkephalin, endorphin, gastrin glucagon, melatonin, motilin, neurokinin A, neurokinin B, orexin, oxytocin, pancreatic peptide, peptide YY, substance P, or vasoactive intestinal peptide blocking antibody.
  • the neuropeptide YY CGRP
  • neuromodulating agent is a neuropeptide Y blocking antibody.
  • the neuromodulating agent is a neuropeptide Y blocking antibody.
  • neuromodulating agent is a CGRP blocking antibody.
  • the CGRP blocking antibody is an antibody listed in Table 4.
  • the neuromodulating agent is a
  • the neurotransmission modulator is a neurotransmission modulator.
  • the neurotransmission modulator is a neurotransmission modulator.
  • neurotransmitter listed in Tables 1 A-1 B a neurotransmitter encoded by a gene in Table 7, an agonist or an antagonist of a neurotransmitter of neurotransmitter receptor listed in Tables 1 A-1 B or encoded by a gene in Table 7, a neurotransmission modulator listed in Table 2M, a modulator of a biosynthesis, channel, ligand receptor, signaling, structural, synaptic, vesicular, or transporter protein encoded by a gene in Table 7, a channel or transporter protein encoded by a gene in Table 8, or a neurotoxin listed in Table 3.
  • the agonist or antagonist is an agonist or antagonist listed in Tables 2A- 2K.
  • the neuromodulating agent is a neuropeptide signaling modulator.
  • the neuropeptide signaling modulator is a neuropeptide listed in Tables 1 A-1 B or encoded by a gene in Table 7 or analog thereof, an agonist or antagonist of a neuropeptide or neuropeptide receptor listed in in Tables 1 A-1 B or encoded by a gene in Table 7, or a modulator of a biosynthesis, ligand, receptor, or signaling protein encoded by a gene in Table 7.
  • the neuropeptide has at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity to the neuropeptide sequence referenced by accession number or Entrez Gene ID in Tables 1 A-1 B or Table 7.
  • the agonist or antagonist is an agonist or antagonist listed in Table 2A or 2L.
  • the neuromodulating agent is a neuronal growth factor modulator.
  • the neuronal growth factor modulator is a neuronal growth factor listed in Table 1 C or encoded by a gene in Table 7 or an analog thereof, or a modulator of a ligand, receptor, structural, synaptic, or signaling protein encoded by a gene in Table 7.
  • the neuronal growth factor has at least 70%, 75%, 80%, 85%, 90%, 90%, 98%, or 99% identity to the neuronal growth factor sequence referenced by accession number or Entrez Gene ID in Table 1 C or Table 7.
  • the neuronal growth factor modulator is an antibody listed in Table 5.
  • the neuronal growth factor modulator is an agonist or antagonist listed in Table 6. In some embodiments, the neuronal growth factor modulator is etanercept, thalidomide, lenalidomide, pomalidomide, pentoxifylline, bupropion, DOI, disitertide, or trabedersen.
  • the neuromodulating agent is a neurome gene expression modulator.
  • the neurome gene expression modulator increases or decreases the expression of a neurome gene in Table 7.
  • the neuromodulating agent modulates the expression of a neurome gene in Table 7 or the activity of a protein encoded by a neurome gene in Table 7.
  • the neuromodulating agent modulates the expression or activity of a chemokine, chemokine receptor, or immune cell trafficking molecule in Tables 10 or 1 1 .
  • the neuromodulating agent is selected from the group including a neurotransmitter, a neuropeptide, an antibody, a small molecule, a DNA molecule, a RNA molecule, a gRNA, and a viral vector.
  • the antibody is a blocking or neutralizing antibody.
  • the RNA molecule is an mRNA or an inhibitory RNA.
  • the viral vector is selected from the group including an adeno-associated virus (AAV), an adenovirus, a parvovirus, a coronavirus, a rhabdovirus, a paramyxovirus, a picornavirus, an alphavirus, a herpes virus, a poxvirus, and a lentivirus.
  • AAV adeno-associated virus
  • the herpes virus is a replication deficient herpes virus.
  • the neuromodulating agent does not cross the blood brain barrier.
  • the neuromodulating agent has been modified to prevent blood brain barrier crossing by conjugation to a targeting moiety, formulation in a particulate delivery system, addition of a molecular adduct, or through modulation of its size, polarity, flexibility, or lipophilicity.
  • the neuromodulating agent does not have a direct effect on the central nervous system or gut.
  • the neuromodulating agent is administered locally. In some embodiments, the neuromodulating agent is administered to or near a lymph node.
  • the method further includes administering a second therapeutic agent.
  • the second therapeutic agent is a disease-modifying anti-rheumatic drug (DMARD), a biologic response modifier (a type of DMARD), a corticosteroid, a nonsteroidal anti-inflammatory medication (NSAID), prednisone, prednisolone, methylprednisolone, methotrexate, hydroxycholorquine, sulfasalazine, leflunomide, cyclophosphamide, azathioprine, tofacitinib, adalimumab, abatacept, anakinra, kineret, certolizumab, etanercept, golimumab, infliximab, rituximab tocilizumab, an antiviral compound, a nucleoside-analog reverse transcriptase inhibitor (NRTI), a non-nupramine, a nucleoside-analog
  • the method further includes measuring cytokine levels after administration of the neuromodulating agent.
  • the method further includes measuring one or more immune cell markers after administration of the neuromodulating agent.
  • the method further includes measuring the expression of one or more neurome genes in Table 7 after administration of the neuromodulating agent.
  • the method further includes measuring cytokine levels before administration of the neuromodulating agent. In some embodiments of any of the above aspects, wherein the method further includes measuring one or more immune cell markers before administration of the neuromodulating agent.
  • the one or more immune cell markers is a marker listed in Table 9.
  • the method further includes profiling an immune cell for expression of one or more neurome genes in Table 7 before administration of the neuromodulating agent. In some embodiments, the method further includes selecting a neuromodulating agent based on the profiling results.
  • the one or more neurome genes in Table 7 is a channel, transporter, neurotransmitter, neuropeptide, neurotrophic, signaling, synaptic, structural, ligand, receptor, biosynthesis, other, or vesicular gene.
  • the subject is not diagnosed as having a neuropsychiatric disorder.
  • the subject is not diagnosed as having high blood pressure or a cardiac condition.
  • neuromodulating agent is administered in an amount sufficient to increase lymph node innervation, increase nerve firing in a lymph node, increase the development of HEVs or TLOs, increase immune cell migration, increase immune cell proliferation, increase immune cell recruitment, increase immune cell lymph node homing, increase immune cell lymph node egress, increase immune cell differentiation, increase immune cell activation, increase immune cell polarization, increase immune cell cytokine production, increase immune cell degranulation, increase immune cell maturation, increase immune cell ADCC, increase immune cell ADCP, or increase immune cell antigen presentation.
  • the neuromodulating agent is administered in an amount sufficient to decrease lymph node innervation, decrease nerve firing in a lymph node, decrease the development of HEVs or TLOs, decrease immune cell migration, decrease immune cell proliferation, decrease immune cell recruitment, decrease immune cell lymph node homing, decrease immune cell lymph node egress, decrease immune cell differentiation, decrease immune cell activation, decrease immune cell polarization, decrease immune cell cytokine production, decrease immune cell degranulation, decrease immune cell maturation, decrease immune cell ADCC, decrease immune cell ADCP, or decrease immune cell antigen presentation.
  • the neuromodulating agent is administered in an amount sufficient to treat the autoimmune or inflammatory condition or infection, reduce symptoms of an autoimmune or inflammatory condition, reduce inflammation, reduce auto-antibody levels, increase organ function, decrease rate or number of relapses or flare-ups, reduce viral load, or control infection.
  • agonist refers to an agent (e.g., a neurotransmitter, neuropeptide, small molecule, or antibody) that increases receptor activity.
  • An agonist may activate a receptor by directly binding to the receptor, by acting as a cofactor, by modulating receptor conformation (e.g., maintaining a receptor in an open or active state).
  • An agonist may increase receptor activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.
  • An agonist may induce maximal receptor activation or partial activation depending on the concentration of the agonist and its mechanism of action.
  • analog refers to a protein of similar nucleotide or amino acid composition or sequence to any of the proteins or peptides of the invention, allowing for variations that do not have an adverse effect on the ability of the protein or peptide to carry out its normal function (e.g., bind to a receptor or initiate neurotransmitter or neuropeptide signaling). Analogs may be the same length, shorter, or longer than their corresponding protein or polypeptide.
  • Analogs may have about 60% (e.g., about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, about 86%, about 88%, about 90%, about 92%, about 94%, about 96%, about 98%, or about 99%) identity to the amino acid sequence of the naturally occurring protein or peptide.
  • An analog can be a naturally occurring protein or polypeptide sequence that is modified by deletion, addition, mutation, or substitution of one or more amino acid residues.
  • an antagonist refers to an agent (e.g., a neurotransmitter, neuropeptide, small molecule, or antibody) that reduces or inhibits receptor activity.
  • An antagonist may reduce receptor activity by directly binding to the receptor, by blocking the receptor binding site, by modulating receptor conformation (e.g., maintaining a receptor in a closed or inactive state).
  • An antagonist may reduce receptor activity by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.
  • An antagonist may also completely block or inhibit receptor activity. Antagonist activity may be any agent (e.g., a neurotransmitter, neuropeptide, small molecule, or antibody) that reduces or inhibits receptor activity.
  • An antagonist may reduce receptor activity by directly binding to the receptor, by blocking the receptor binding site, by modulating receptor conformation (e.g., maintaining a receptor in a closed or inactive state).
  • An antagonist may reduce receptor activity by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%
  • antibody comprises at least the variable domain of a heavy chain, and normally comprises at least the variable domains of a heavy chain and of a light chain of an
  • Antibodies and antigen-binding fragments, variants, or derivatives thereof include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies.
  • Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.
  • cardiac condition refers to a medical condition directly affecting the heart or circulatory system. Cardiac conditions include abdominal aortic aneurysm, arrhythmia (e.g., supraventricular tachycardia, inappropriate sinus tachycardia, atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation), angina, atherosclerosis, brugada syndrome, cardiac arrest, cardiomyopathy, cardiovascular disease, congenital heart disease, coronary heart disease,
  • arrhythmia e.g., supraventricular tachycardia, inappropriate sinus tachycardia, atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation
  • angina e.g., atherosclerosis, brugada syndrome, cardiac arrest, cardiomyopathy, cardiovascular disease, congenital heart disease, coronary heart disease,
  • CVPT catecholaminergic polymorphic ventricular tachycardia
  • familial hypercholesterolaemia heart attack, heart failure, heart block
  • heart valve disease e.g., heart murmur, valve stenosis, mitral valve prolapse, and heart valve regurgitation
  • inherited heart conditions long QT syndrome
  • PCCD progressive cardiac conduction deficit
  • pericarditis venous thromboembolism, peripheral artery disease, and stroke.
  • cell type refers to a group of cells sharing a phenotype that is statistically separable based on gene expression data. For instance, cells of a common cell type may share similar structural and/or functional characteristics, such as similar gene activation patterns and antigen presentation profiles. Cells of a common cell type may include those that are isolated from a common tissue (e.g., epithelial tissue, neural tissue, connective tissue, or muscle tissue) and/or those that are isolated from a common organ, tissue system, blood vessel, or other structure and/or region in an organism.
  • tissue e.g., epithelial tissue, neural tissue, connective tissue, or muscle tissue
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • an agent that "does not cross the blood brain barrier” is an agent that does not significantly cross the barrier between the peripheral circulation and the brain and spinal cord. This can also be referred to as “blood brain barrier impermeable” agent. Agents will have a limited ability to cross the blood brain barrier if they are not lipid soluble or have a molecular weight of over 600 Daltons.
  • Agents that typically cross the blood brain barrier can be modified to become blood brain barrier impermeable based on chemical modifications that increase the size or alter the hydrophobicity of the agent, packaging modifications that reduce diffusion (e.g., packaging an agent within a microparticle or nanoparticle), and conjugation to biologies that direct the agent away from the blood brain barrier (e.g., conjugation to a pancreas-specific antibody).
  • An agent that does not cross the blood brain barrier is an agent for which 30% or less (e.g., 30%, 25%, 20%, 15%, 10%, 5%, 2% or less) of the administered agent crosses the blood brain barrier.
  • an agent that "does not have a direct effect on the central nervous system (CNS) or gut” is an agent that does not directly alter neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut when administered according to the methods described herein. This may be assessed by administering the agents to animal models and performing electrophysiological recordings or immunohistochemical analysis. An agent will be considered not to have a direct effect on the CNS or gut if administration according to the methods described herein has an effect on
  • neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut that is 50% or less (e.g., 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less) of the effect observed if the same agent is administered directly to the CNS or gut.
  • the terms "effective amount,” “therapeutically effective amount,” and a “sufficient amount” of composition, vector construct, viral vector or cell described herein refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating an autoimmune disorder, inflammation, or infection, it is an amount of the composition, vector construct, viral vector or cell sufficient to achieve a treatment response as compared to the response obtained without administration of the composition, vector construct, viral vector or cell.
  • a "therapeutically effective amount" of a composition, vector construct, viral vector or cell of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of a composition, vector construct, viral vector or cell of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regime may be adjusted to provide the optimum therapeutic response.
  • high blood pressure refers to a chronic medical condition in which the systemic arterial blood pressure is elevated. It is classified as blood pressure above 140/90 mmHg.
  • the terms “increasing” and “decreasing” refer to modulating resulting in, respectively, greater or lesser amounts, of function, expression, or activity of a metric relative to a reference.
  • the amount of a marker of a metric e.g., T cell polarization
  • the amount of a marker of a metric may be increased or decreased in a subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% or more relative to the amount of the marker prior to administration.
  • the metric is measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least one week, one month, 3 months, or 6 months, after a treatment regimen has begun.
  • the term "innervated” refers to a tissue (e.g., a lymph node) that contains nerves.
  • Imaging refers to the process of nerves entering a tissue.
  • locally or “local administration” means administration at a particular site of the body intended for a local effect and not a systemic effect.
  • local administration are epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect.
  • a “neuromodulating agent” is an agent that affects a nerve impulse, a nerve function, one or more components of a neural pathway, neural structure, function, or activity in a neuron or a cell of an innervated tissue, e.g., in the peripheral nervous system.
  • a neuromodulating agent may, e.g., increase or decrease neurogenesis; potentiate or inhibit the transmission of a nerve impulse;
  • a neuromodulating agent may be a neuropeptide, a neurotoxin, or a neurotransmitter, and may be any type of agent such as a small molecule (e.g. a neuropeptide or neurotransmitter agonist or antagonist), a peptide, a protein (e.g., an antibody or receptor fusion protein) or a nucleic acid (e.g., a therapeutic mRNA).
  • Neuromodulating agents include neurotransmission modulators, neuropeptide signaling modulators, neuronal growth factor modulators, and neurome gene expression modulators.
  • neurome gene refers to a gene expressed by a cell or tissue of the nervous system.
  • a list of exemplary neurome genes is provided in Tables 1 A-1 C, Table 7, and Table 8.
  • Non-nervous system cells and tissues e.g., immune cells
  • the invention includes methods of profiling non-nervous system cells and tissues for neurome gene expression, modulating neurome gene expression in in non-nervous system cells and tissues, and treating autoimmune or inflammatory disorders or infection based on neurome gene expression in in non- nervous system cells and tissues.
  • neurome gene expression modulator refers to a neuromodulating agent that affects gene expression (e.g., gene transcription, gene translation, or protein levels) of one or more neurome genes.
  • a neurome gene expression modulator may increase or decrease gene expression by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or more.
  • Neurome gene expression modulators may increase gene expression through epigenetic modifications (e.g., demethylation or acetylation), post-translational modifications (e.g., reducing ubiquitination, or altering sumoylation or phosphorylation), by increasing mRNA translation and stability, or through delivery of exogenous genetic material (e.g., a viral vector expressing a gene of interest).
  • epigenetic modifications e.g., demethylation or acetylation
  • post-translational modifications e.g., reducing ubiquitination, or altering sumoylation or phosphorylation
  • exogenous genetic material e.g., a viral vector expressing a gene of interest.
  • Neurome gene expression modulators may decrease gene expression through epigenetic modifications (e.g., methylation or deacetylation), post-translational modifications (e.g., increasing ubiquitination, or altering sumoylation or phosphorylation), or by decreasing mRNA translation and stability (e.g., using miRNA, siRNA, shRNA, or other therapeutic RNAs).
  • epigenetic modifications e.g., methylation or deacetylation
  • post-translational modifications e.g., increasing ubiquitination, or altering sumoylation or phosphorylation
  • mRNA translation and stability e.g., using miRNA, siRNA, shRNA, or other therapeutic RNAs.
  • Neuronal growth factor modulator refers to a neuromodulating agent that regulates neuronal growth, development, or survival.
  • Neuronal growth factors include proteins that promote neurogenesis, neuronal growth, and neuronal differentiation (e.g., neurotrophic factors NGF, NT3, BDNF, CNTF, and GDNF), proteins that promote neurite outgrowth (e.g., axon or dendrite outgrowth or stabilization), or proteins that promote synapse formation (e.g., synaptogenesis, synapse assembly, synaptic adhesion, synaptic maturation, synaptic refinement, or synaptic stabilization).
  • neurotrophic factors include proteins that promote neurogenesis, neuronal growth, and neuronal differentiation (e.g., neurotrophic factors NGF, NT3, BDNF, CNTF, and GDNF), proteins that promote neurite outgrowth (e.g., axon or dendrite outgrowth or stabilization), or proteins that promote synapse formation (e
  • a neuronal growth factor modulator may block one or more of these processes (e.g., through the use of antibodies that block neuronal growth factors or their receptors) or promote one or more of these processes (e.g., through the use of these proteins or analogs or peptide fragments thereof).
  • Exemplary neuronal growth factors are listed in Table 1 C.
  • neuropeptide signaling modulator refers to a neuromodulating agent that either induces or increases neuropeptide signaling, or decreases or blocks neuropeptide signaling.
  • Neuropeptide signaling modulators can increase or decrease neuropeptide signaling by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neuropeptides and neuropeptide receptors are listed in Tables 1 A-1 B.
  • Neuropeptide signaling modulators that induce or increase neuropeptide signaling include neuropeptides and analogs and fragments thereof, agents that increase neuropeptide receptor activity (e.g., neuropeptide agonists), and agents that reduce neuropeptide degradation or reuptake.
  • Neuropeptide signaling modulators that decrease or block neuropeptide signaling include agents that reduce or inhibit neuropeptide receptor activity (e.g., neuropeptide antagonists), agents that bind to neuropeptides or block their interaction with receptors (e.g.,
  • neuropeptide blocking antibodies or agents that increase neuropeptide degradation or clearance.
  • neuropeptide agonists and antagonists are listed in Tables 2A and 2L.
  • neuropsychiatric disorder refers to a psychiatric or mental disorder that may cause suffering or an impaired ability to function.
  • a neuropsychiatric disorder is a syndrome characterized by clinically significant disturbance in an individual's cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. Neuropsychiatric disorders may be diagnosed by psychiatrists, psychologists, neurologists, or physicians.
  • Neuropsychiatric disorders include mood disorders (e.g., depression, bipolar depression, major depressive disorder), psychotic disorders (e.g., schizophrenia, schizoaffective disorder), personality disorders (e.g., borderline personality disorder, obsessive compulsive personality disorder, narcissistic personality disorder), eating disorders, sleep disorders, sexual disorders, anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, post- traumatic stress disorder), developmental disorders (e.g., autism, attention deficit disorder, attention deficit hyperactivity disorder), benign forgetfulness, childhood learning disorders, Alzheimer's disease, addiction, and others listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM).
  • mood disorders e.g., depression, bipolar depression, major depressive disorder
  • psychotic disorders e.g., schizophrenia, schizoaffective disorder
  • personality disorders e.g., borderline personality disorder, obsessive compulsive personality disorder, narcissistic personality disorder
  • eating disorders e.g., sleep disorders, sexual
  • neurotransmission modulator refers to a neuromodulating agent that either induces or increases neurotransmission or decreases or blocks neurotransmission.
  • Neurotransmission modulators can increase or decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmitters and neurotransmitter receptors are listed in Tables 1 A-1 B. Neurotransmission modulators may increase neurotransmission by increasing neurotransmitter synthesis or release, preventing neurotransmitter reuptake or degradation, increasing neurotransmitter receptor activity, increasing neurotransmitter receptor synthesis or membrane insertion, decreasing neurotransmitter degradation, and regulating neurotransmitter receptor
  • Neurotransmission modulators that increase neurotransmission include neurotransmitters and analogs thereof and neurotransmitter receptor agonists. Neurotransmission modulators may decrease neurotransmission by decreasing neurotransmitter synthesis or release, increasing
  • Neurotransmitter reuptake or degradation decreasing neurotransmitter receptor activity, decreasing neurotransmitter receptor synthesis or membrane insertion, increasing neurotransmitter degradation, regulating neurotransmitter receptor conformation, and disrupting the pre- or postsynaptic machinery.
  • Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release.
  • percent (%) sequence identity refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence that are identical to the amino acid (or nucleic acid) residues of a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity (e.g., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software.
  • a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% sequence identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence.
  • the length of the candidate sequence aligned for comparison purposes may be, for example, at least 30%, (e.g., 30%, 40, 50%, 60%, 70%, 80%, 90%, or 100%) of the length of the reference sequence.
  • a "pharmaceutical composition” or “pharmaceutical preparation” is a composition or preparation, having pharmacological activity or other direct effect in the mitigation, treatment, or prevention of disease, and/or a finished dosage form or formulation thereof and which is indicated for human use.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • proliferation refers to an increase in cell numbers through growth and division of cells.
  • sample refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells) isolated from a subject.
  • a specimen e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells
  • the terms "subject” and "patient” refer to an animal (e.g., a mammal, such as a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art.
  • a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
  • Treatment and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder.
  • This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy).
  • Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition ; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “Ameliorating” or “palliating” a disease or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • activation refers to the response of an immune cell to a perceived insult.
  • immune cells When immune cells become activated, they proliferate, secrete pro-inflammatory cytokines, differentiate, present antigens, become more polarized, and become more phagocytic and cytotoxic.
  • Factors that stimulate immune cell activation include pro-inflammatory cytokines, pathogens, and non-self antigen presentation (e.g., antigens from pathogens presented by dendritic cells, macrophages, or B cells).
  • ADCC antibody-dependent cell mediated cytotoxicity
  • cytotoxic effector cell refers to the killing of an antibody-coated target cell by a cytotoxic effector cell through a non-phagocytic process, characterized by the release of the content of cytotoxic granules or by the expression of cell death-inducing molecules.
  • ADCC is triggered through interaction of target-bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs), glycoproteins present on the effector cell surface that bind the Fc region of immunoglobulins (Ig).
  • Effector cells that mediate ADCC include natural killer (NK) cells, monocytes, macrophages, neutrophils, eosinophils and dendritic cells.
  • NK natural killer
  • antibody-dependent cell mediated phagocytosis and “antibody-dependent cellular phagocytosis” (ADCP) refer to the phagocytosis (e.g., engulfment) of an
  • ADCP antibody-coated target cell by immune cells (e.g., phagocytes).
  • ADCP is triggered through interaction of target-bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs, e.g.,
  • FcyRlla, FcyRllla, and FcyRI glycoproteins present on the effector cell surface that bind the Fc region of immunoglobulins (Ig).
  • Effector cells that mediate ADCP include monocytes, macrophages, neutrophils, and dendritic cells.
  • antigen presentation refers to a process in which fragments of antigens are displayed on the cell surface of immune cells. Antigens are presented to T cells and B cells to stimulate an immune response. Antigen presenting cells include dendritic cells, B cells, and macrophages. Mast cells and neutrophils can also be induced to present antigens.
  • anti-inflammatory cytokine refers to a cytokine produced or secreted by an immune cell that reduces inflammation.
  • Immune cells that produce and secrete anti-inflammatory cytokines include T cells (e.g., Th cells) macrophages, B cells, and mast cells.
  • Anti-inflammatory cytokines include IL4, IL-10, IL-1 1 , IL-13, interferon alpha (IFNa) and transforming growth factor-beta (TGFp).
  • chemokine refers to a type of small cytokine that can induce directed chemotaxis in nearby cells.
  • Classes of chemokines include CC chemokines, CXC chemokines, C chemokines, and CX3C chemokines.
  • Chemokines can regulate immune cell migration and homing, including the migration and homing of monocytes, macrophages, T cells, mast cells, eosinophils, and neutrophils.
  • Chemokines responsible for immune cell migration include CCL19, CCL21 , CCL14, CCL20, CCL25, CCL27, CXCL12, CXCL13, CCR9, CCR1 0, and CXCR5.
  • Chemokines that can direct the migration of inflammatory leukocytes to sites of inflammation or injury include CCL2, CCL3, CCL5, CXCL1 , CXCL2, and CXCL8.
  • cytokine refers to a small protein involved in cell signaling. Cytokines can be produced and secreted by immune cells, such as T cells, B cells, macrophages, and mast cells, and include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors.
  • cytokine production refers to the expression, synthesis, and secretion (e.g., release) of cytokines by an immune cell.
  • cytotoxicity refers to the ability of immune cells to kill other cells. Immune cells with cytotoxic functions release toxic proteins (e.g., perforin and granzymes) capable of killing nearby cells. Natural killer cells and cytotoxic T cells (e.g., CD8+ T cells) are the primary cytotoxic effector cells of the immune system, although dendritic cells, neutrophils, eosinophils, mast cells, basophils, macrophages, and monocytes have been shown to have cytotoxic activity.
  • the term “differentiation” refers to the developmental process of lineage commitment.
  • a “lineage” refers to a pathway of cellular development, in which precursor or “progenitor” cells undergo progressive physiological changes to become a specified cell type having a characteristic function (e.g., nerve cell, immune cell, or endothelial cell). Differentiation occurs in stages, whereby cells gradually become more specified until they reach full maturity, which is also referred to as “terminal differentiation.”
  • a “terminally differentiated cell” is a cell that has committed to a specific lineage, and has reached the end stage of differentiation (i.e., a cell that has fully matured).
  • differentiated is meant a cell that expresses one or more markers or other characteristic of a cell of a particular lineage.
  • the term "degranulation” refers to a cellular process in which molecules, including antimicrobial and cytotoxic molecules, are released from intracellular secretory vesicles called granules. Degranulation is part of the immune response to pathogens and invading microorganisms by immune cells such as granulocytes (e.g., neutrophils, basophils, and eosinophils), mast cells, and lymphocytes (e.g., natural killer cells and cytotoxic T cells).
  • the molecules released during degranulation vary by cell type and can include molecules designed to kill the invading pathogens and microorganisms or to promote an immune response, such as inflammation.
  • immune dysregulation refers to a condition in which the immune system is disrupted or responding to an insult. Immune dysregulation includes aberrant activation (e.g., autoimmune disease), activation in response to an injury or disease (e.g., disease-associated
  • Immune dysregulation also includes under-activation of the immune system (e.g., immunosuppression). Immune dysregulation can be treated using the methods and compositions described herein to direct immune cells to carry out beneficial functions and reduce harmful activities (e.g., reducing activation and proinflammatory cytokine secretion in subjects with autoimmune disease).
  • the term "modulating an immune response” refers to any alteration in a cell of the immune system or any alteration in the activity of a cell involved in the immune response. Such regulation or modulation includes an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes that can occur within the immune system.
  • Cells involved in the immune response include, but are not limited to, T lymphocytes (T cells), B lymphocytes (B cells), natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils.
  • T cells T lymphocytes
  • B cells B lymphocytes
  • NK natural killer cells
  • macrophages eosinophils
  • mast cells dendritic cells and neutrophils.
  • lymph node egress refers to immune cell exit from the lymph nodes, which occurs during immune cell recirculation.
  • Immune cells that undergo recirculation include lymphocytes (e.g., T cells, B cells, and natural killer cells), which enter the lymph node from blood to survey for antigen and then exit into lymph and return to the blood stream to perform antigen surveillance.
  • lymphocytes e.g., T cells, B cells, and natural killer cells
  • lymph node homing refers to directed migration of immune cells to a lymph node.
  • Immune cells that return to lymph nodes include T cells, B cells, macrophages, and dendritic cells.
  • migraine refers to the movement of immune cells throughout the body.
  • Immune cells can migrate in response to external chemical and mechanical signals. Many immune cells circulate in blood including peripheral blood mononuclear cells (e.g., lymphocytes such as T cells, B cells, and natural killer cells), monocytes, macrophages, dendritic cells, and polymorphonuclear cells (e.g., neutrophils and eosinophils). Immune cells can migrate to sites of infection, injury, or inflammation, or back to the lymph nodes.
  • peripheral blood mononuclear cells e.g., lymphocytes such as T cells, B cells, and natural killer cells
  • monocytes e.g., monocytes, macrophages, dendritic cells, and polymorphonuclear cells (e.g., neutrophils and eosinophils).
  • neutrophils and eosinophils e.g., neutrophils and eosinophils
  • phagocytosis refers to the process in which a cell engulfs or ingests material, such as other cells or parts of cells (e.g., bacteria), particles, or dead or dying cells.
  • a cell that capable of performing this function is called a phagocyte.
  • Immune phagocytes include neutrophils, monocytes, macrophages, mast cells, B cells, eosinophils, and dendritic cells.
  • polarization refers to the ability of an immune cell to shift between different functional states. A cell that is moving toward one of two functional extremes is said to be in the process of becoming more polarized.
  • the term polarization is often used to refer to macrophages, which can shift between states known as M1 and M2.
  • M1 or classically activated, macrophages secrete proinflammatory cytokines (e.g., IL-12, TNF, IL-6, IL-8, IL-1 B, MCP-1 , and CCL2), are highly phagocytic, and respond to pathogens and other environmental insults. M1 macrophages can also be detected by expression of Nos2.
  • macrophages secrete a different set of cytokines (e.g., IL-10) and are less phagocytic.
  • M2 macrophages can detected by expression of Arg1 , IDO, PF4, CCL24, IL10, and IL4Ra. Cells become polarized in response to external cues such as cytokines, pathogens, injury, and other signals in the tissue microenvironment.
  • pro-inflammatory cytokine refers to a cytokine secreted from immune cells that promotes inflammation.
  • Immune cells that produce and secrete pro-inflammatory cytokines include T cells (e.g., Th cells) macrophages, B cells, and mast cells.
  • Pro-inflammatory cytokines include interleukin-1 (IL-1 , e.g., IL-1 ⁇ ), IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-18, tumor necrosis factor (TNF, e.g., TNFa), interferon gamma (IFNy), and granulocyte macrophage colony stimulating factor (GMCSF).
  • IL-1 interleukin-1
  • TNFa tumor necrosis factor
  • IFNy interferon gamma
  • GMCSF granulocyte macrophage colony stimulating factor
  • pro-survival cytokine refers to a cytokine that promotes the survival of immune cells (e.g., T cells).
  • Pro-survival cytokines include IL-2, IL-4, IL-6, IL-7, and IL-15.
  • the term "recruitment” refers to the re-distribution of immune cells to a particular location (e.g., the site of infection, injury, or inflammation).
  • Immune cells that can undergo this redistributed and be recruited to sites of injury or disease include monocytes, macrophages, T cells, B cells, dendritic cells, and natural killer cells.
  • FIGS. 1 A-1 C are a series of graphs showing that dopamine stimulation induces T cell production of pro-inflammatory cytokines.
  • Dopamine was applied to primary human T cells isolated from healthy donors and maintained in culture. Low sub-nanomolar concentrations of dopamine induced an increase in the production of the pro-inflammatory cytokines IFNy, IL-5, and IL-13 at 72 hours post treatment.
  • FIGS. 2A-2B are a series of graphs showing that dopamine stimulation induces T cell production of pro-inflammatory cytokines.
  • Dopamine was applied to primary human T cells isolated from healthy donors and maintained in culture. Low sub-nanomolar concentrations of dopamine induced an increase in the production of the pro-inflammatory cytokines IL-6 and IL-10 at 72 hours post treatment.
  • FIGS. 3A-3B are a series of graphs showing that dopamine stimulation induces T cell production of pro-survival cytokines.
  • Dopamine and the synthetic dopamine agonist quinpirole were applied to primary human T cells isolated from healthy donors and maintained in culture. Stimulation of T cells with dopamine and the synthetic dopamine agonist quinpirole induced an increase in T cell production of the pro-survival cytokine IL-2.
  • Dopamine induced an increase in IL-2 production at 24 and 48 hours post- treatment, while quinpirole induced an increase at all time points tested.
  • FIG. 4 is a series of graphs showing that isoproterenol modulates T cell cytokine production.
  • Adrenergic agonist isoproterenol was applied to primary human T cells isolated from healthy donors and maintained in culture. Stimulation of T cells with the adrenergic agonist isoproterenol decreased production of pro-inflammatory cytokine IFNy in T cells from two different donors at multiple time points.
  • FIG. 5 is a series of graphs showing that isoproterenol modulates T cell cytokine production.
  • Adrenergic agonist isoproterenol was applied to primary human T cells isolated from healthy donors and maintained in culture. Stimulation of T cells with the adrenergic agonist isoproterenol decreased production of pro-inflammatory cytokine TNFa in T cells from two different donors at multiple time points.
  • FIGS. 6A-6C are a series of graphs showing that isoproterenol modulates T cell cytokine production.
  • Adrenergic agonist isoproterenol was applied to primary human T cells isolated from healthy donors and maintained in culture. Stimulation of T cells with the adrenergic agonist isoproterenol decreased production of pro-inflammatory cytokines IFNy (FIG. 6A), TNFa (FIG. 6B), and IL-1 0 (FIG. 6C) in T cells from two different donors at 72 hours.
  • FIG. 7 is a graph showing that neuropeptide Y modulates T cell cytokine production.
  • Neuropeptide Y was applied to primary human T cells isolated from healthy donors and maintained in culture. Stimulation of T cells with Neuropeptide Y induced an increase in IL-4 at sub-nanomolar concentrations at 48 hours post-treatment.
  • FIGS. 8A-8D are a series of graphs showing that hock injection of dopaminergic pathway modulators in mice modulates T cell migration.
  • C57BL/6J mice were injected in each hock with 50 ⁇ _ of the immunostimulant CpG ODN (0.1 nmol), 50 ⁇ _ of the dopaminergic agonist quinpirole (0.1 nmol), or with 25 ⁇ _ dopaminergic antagonist (Haloperidol - 48.5 nmol) followed by 25 ⁇ _ quinpirole (0.1 nmol).
  • Hock injection of dopamine agonist quinpirole increased the number of migratory phenotype CCR7+ T cells in the lymph node (FIGS.
  • Neuromodulating agents described herein can surprisingly have immune effects, such as effects on T cell polarization, T cell activation, T cell proliferation, cytotoxic T cell activation, circulating monocytes, peripheral blood hematopoietic stem cells, immune cell numbers, macrophage polarization, macrophage phagocytosis, antibody-dependent cell-mediated phagocytosis (ADCP), macrophage activation, macrophage polarization, antigen presentation, antigen presenting cell migration, lymph node immune cell homing and cell egress, NK cell activation, antibody-dependent cell-mediated cytotoxicity (ADCC), mast cell degranulation, neutrophil recruitment, eosinophil recruitment, NKT cell activation, B cell activation, and regulatory T cell differentiation. It has been found that neuromodulating agents thus can have a therapeutic effect on inflammatory and autoimmune conditions.
  • Neuromodulating agents described herein can agonize or inhibit genes or proteins in
  • Neuromodulatory signaling pathway genes are listed in Tables 1 A-C (column 1 ). Additional neurome genes (e.g., genes expressed by a nervous system cell or tissue) are listed in Table 7 and Table 8. The level, activity and/or function of such genes and the proteins they encode can be modulated by pharmaceutical compositions comprising agents described herein. Neuromodulating agents also include neurotransmitter and neuropeptide ligands listed in Table 1 B and neuronal growth factors listed in Table 1 C.
  • Neuromodulating agents can be divided into four major categories: 1 ) neurotransmission modulators (e.g., agents that increase or decrease neurotransmission, such as neurotransmitter agonists or antagonists or neurotoxins), 2) neuropeptide signaling modulators (e.g., neuropeptides and
  • neuropeptide agonists or antagonists e.g., 3) neuronal growth factor modulators (e.g., neuronal growth factors or agents that agonize or antagonize neuronal growth factor signaling), and 4) neurome gene expression modulators (e.g., agents that modulate expression of a gene listed in Table 7 or Table 8).
  • neuropeptide agonists or antagonists e.g., a neuropeptide agonists or antagonists
  • neuronal growth factor modulators e.g., neuronal growth factors or agents that agonize or antagonize neuronal growth factor signaling
  • neurome gene expression modulators e.g., agents that modulate expression of a gene listed in Table 7 or Table 8.
  • HCRTR1 Neuropeptide/Orexin Receptor 043613 3061
  • Neurophysin 1 Neurohypophyseals Ligand P01 178
  • EphA5 Receptor P54756 2044 Gene Type Accession Entrez Number Gene ID
  • the neuromodulating agent is a neurotransmission modulator (e.g., an agent that increases or decreases neurotransmission).
  • the neuromodulating agent is a neurotransmitter or neurotransmitter receptor listed in Table 1 A, 1 B, Table 7, or Table 8, a modulator of a channel or transporter encoded by a gene in Table 7, or an agonist or antagonist listed in Tables 2A-2K for a corresponding neurotransmitter pathway member.
  • the neurotransmission modulator is a neurotransmission modulator listed in Table 2M.
  • Neuromodulating agents that increase neurotransmission include neurotransmitters and neurotransmitter receptors listed in Tables 1 A, 1 B, Table 7, and Table 8 and analogs thereof, and neurotransmitter agonists (e.g., small molecules that agonize a neurotransmitter receptor listed in Table 1 A or encoded by a gene in Table 7 or Table 8). Exemplary agonists are listed in Tables 2A-2K.
  • neurotransmission is increased via administration, local delivery, or stabilization of neurotransmitters (e.g., ligands listed in Tables 1 A, 1 B, and Table 7).
  • Neurotransmission modulators that increase neurotransmission also include agents that increase neurotransmitter synthesis or release (e.g., agents that increase the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, or upregulation, or agents that increase the activity of a synaptic or vesicular protein encoded by a gene in Table 7 via stabilization, overexpression, or upregulation), prevent neurotransmitter reuptake or degradation (e.g., agents that block or antagonize transporters encoded by a gene in Table 7 or Table 8 that remove neurotransmitter from the synaptic cleft), increase
  • agents that increase neurotransmitter synthesis or release e.g., agents that increase the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, or upregulation, or agents that increase the activity of a synaptic or vesicular protein encoded by a gene in Table 7 via stabilization, overexpression, or
  • neurotransmitter receptor activity e.g., agents that increase the activity of a signaling protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, agonism, or upregulation, or agents that upregulate, agonize, or stabilize a neurotransmitter receptor listed in Table 1 A or encoded by a gene in Table 7 or Table 8
  • increase neurotransmitter receptor synthesis or membrane insertion decrease neurotransmitter degradation
  • regulate neurotransmitter receptor conformation e.g., agents that bind to a receptor and keep it in an "open” or “primed” conformation.
  • the neurotransmitter receptor conformation e.g., agents that bind to a receptor and keep it in an "open” or “primed” conformation.
  • neurotransmitter receptor is a channel (e.g., a ligand or voltage gated ion channel listed in Table 7 or Table 8), the activity of which can be increased by agonizing, opening, stabilizing, or overexpressing the channel.
  • Neurotransmission modulators that increase neurotransmission further include agents that stabilize a structural protein encoded by a gene in Table 7.
  • Neurotransmission modulators can increase neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmission modulators are listed in Table 2M.
  • Neuromodulating agents that decrease neurotransmission include neurotransmitter antagonists
  • Neurotransmission modulators that decrease neurotransmission also include agents that decrease neurotransmitter synthesis or release (e.g., agents that decrease the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via inhibition or downregulation, or agents that decrease the activity of a synaptic or vesicular protein encoded by a gene in Table 7 via blocking, disrupting, or downregulating, or antagonizing the protein), increase neurotransmitter reuptake or degradation (e.g., agents that agonize, open, or stabilize transporters encoded by a gene in Table 7 or Table 8 that remove neurotransmitter from the synaptic cleft), decrease neurotransmitter receptor activity (e.g., agents that decrease the activity of a signaling protein encoded by a gene in Table 1 A or Table 7 via blocking or an
  • the neurotransmitter receptor is a channel (e.g., a ligand or voltage gated ion channel listed in Table 7 or Table 8), the activity of which can be decreased by blockade, antagonism, or inverse agonism of the channel.
  • Neurotransmission modulators that decrease neurotransmission further include agents that sequester, block, antagonize, or degrade a
  • Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release. Neurotransmission modulators can decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.
  • the neuromodulating agent is an adrenergic receptor pathway modulator (e.g., a blocker or agonist of an adrenergic receptor listed in Table 1 A or Table 7, e.g., an adrenergic blocker or agonist listed in Table 2A or Table 2B); a cholinergic receptor pathway modulator (e.g., a blocker or agonist of a cholinergic receptor listed in Table 1 A or Table 7, e.g., a cholinergic blocker or agonist listed in Table 2A, 2E, or 2F); a dopamine receptor pathway modulator (e.g., a blocker or agonist of a dopamine receptor listed in Table 1 A or Table 7, e.g., a dopamine blocker or agonist listed in Table 2A or 2C); a serotonin receptor pathway modulator (e.g., a blocker or agonist of a serotonin receptor listed in Table 1 A, Table 7, or Table 8, e

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Abstract

L'invention concerne des méthodes de traitement d'un sujet souffrant ou présentant un risque de développer un état auto-immun ou inflammatoire ou une infection par l'administration d'un agent de neuromodulation.
PCT/US2017/043802 2016-07-26 2017-07-25 Compositions de neuromodulation et méthodes thérapeutiques associées pour le traitement de maladies inflammatoires et auto-immunes WO2018022664A1 (fr)

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US20210154272A1 (en) 2021-05-27
EP3490542A4 (fr) 2020-07-08
EP3506926A4 (fr) 2020-10-14
EP3490542A1 (fr) 2019-06-05
US20210283217A1 (en) 2021-09-16
WO2018022666A1 (fr) 2018-02-01
US20190240293A1 (en) 2019-08-08
WO2018022668A3 (fr) 2019-04-18
EP3506926A1 (fr) 2019-07-10
US20210177823A1 (en) 2021-06-17
WO2018022668A2 (fr) 2018-02-01

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